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【结 构 式】

【分子编号】21682

【品名】2-thienyllithium

【CA登记号】2786-07-4

【 分 子 式 】C4H3LiS

【 分 子 量 】90.07482

【元素组成】C 53.34% H 3.36% Li 7.71% S 35.6%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(II)

The condensation of 2-methylcyclohexanone (I) with 2-thienyl lithium (II) or 2-thienylmagnesium bromide (III) gives cyclohexanol (IV) as a diastereomeric mixture, which was treated with Na-N3 in trichloroacetic acid to yield the azide (V). The reduction of (V) with LiAlH4 or RaNi/iPr-OH affords the corresponding amine (VI), preferentially with the cis-configuration. Finally, this compound is condensed with 1,5-dibromopentane (VII) by means of K2CO3 in acetonitrile to provide the target compound as a diastereomeric mixture. The separation of the cis- and trans- racemates has been performed by HPLC. The optical resolution was performed by a cumbersome crystallization process using CSA and di-p-toluoyltartaric acid.

1 Michaud, M.; et al.; Homochiral structures derived from 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) are potent non-competitive antagonists of glutamate at NMDA receptor sites. Eur J Med Chem 1994, 29, 11, 869.
2 Kamenka, J.-M.; Privat, A.; Chicheportiche, R.; Rondouin, G. (CNRS (Centre National de la Recherche Scientifique)); Pharmaceutical compsns. for neuroprotection containing arylcyclohexylamines. US 5179109; WO 9005524 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 54406 2-Methylcyclohexanone; Tetrahydro-o-cresol; o-Methylcyclohexanone 583-60-8 C7H12O 详情 详情
(II) 21682 2-thienyllithium 2786-07-4 C4H3LiS 详情 详情
(III) 32082 bromo(2-thienyl)magnesium 5713-61-1 C4H3BrMgS 详情 详情
(IV) 54407 (1R,2S)-2-methyl-1-(2-thienyl)cyclohexanol C11H16OS 详情 详情
(V) 54408 (1R,2S)-2-methyl-1-(2-thienyl)cyclohexyl azide; 2-[(1R,2S)-1-azido-2-methylcyclohexyl]thiophene C11H15N3S 详情 详情
(VI) 54409 (1R,2S)-2-methyl-1-(2-thienyl)cyclohexanamine; (1R,2S)-2-methyl-1-(2-thienyl)cyclohexylamine C11H17NS 详情 详情
(VII) 30560 1,5-dibromopentane 111-24-0 C5H10Br2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(II)

Condensation of N-(tert-butoxycarbonyl)phenylalanine methyl ester (I) with 2-thienyllithium (II) in THF at -78 C furnished racemized ketone (III). The N-Boc group of (III) was deprotected with HCl in dioxan to yield aminoketone (IV), which was then condensed with the succinate building block (V) in DMF to afford succinamide (VI). Further deprotection of the tert-butyl ester of (VI) by treatment with trifluoroacetic acid provided carboxylic acid (VII), which was coupled with O-tert-butyldimethylsilyl hydroxylamine (VIII) in the presence of EDC and HOBt to yield, after desilylation, the target hydroxamic acid.

1 Sheppard, G.S.; Florjancic, A.S.; Giesler, J.R.; Xu, L.; Guo, Y.; Davidsen, S.K.; Marcotte, P.A.; Elmore, I.; Albert, D.H.; Terrance, J.M.; Bouska, J.J.; Goodfellow, C.L.; Morgan, D.W.; Summers, J.B.; Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors. Bioorg Med Chem Lett 1998, 8, 22, 3251.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 21673 methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate C15H21NO4 详情 详情
(II) 21682 2-thienyllithium 2786-07-4 C4H3LiS 详情 详情
(III) 21683 tert-butyl 1-benzyl-2-oxo-2-(2-thienyl)ethylcarbamate C18H21NO3S 详情 详情
(IV) 21684 2-amino-3-phenyl-1-(2-thienyl)-1-propanone hydrochloride C13H14ClNOS 详情 详情
(V) 21641 1-(tert-butyl) 4-(2,3,4,5,6-pentafluorophenyl) (2S,3R)-2-allyl-3-isobutylbutanedioate C21H25F5O4 详情 详情
(VI) 21686 tert-butyl (2S)-2-[(1R)-1-([[1-benzyl-2-oxo-2-(2-thienyl)ethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate C28H37NO4S 详情 详情
(VII) 21687 (2S)-2-[(1R)-1-([[1-benzyl-2-oxo-2-(2-thienyl)ethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid C24H29NO4S 详情 详情
(VIII) 21644 (Aminooxy)(tert-butyl)dimethylsilane; O-[tert-Butyl(dimethyl)silyl]hydroxylamine 41879-39-4 C6H17NOSi 详情 详情
Extended Information